Visual loss is one of the most common clinical manifestations of multiple sclerosis (MS). Quantitative assessment of visual impairment in MS trials, however, has been limited to Snellen acuity. The longitudinal visual profile of MS, using sensitive yet clinically practical visual function measures, has not been defined. The extent to which vision is affected over time by immunomodulatory therapies is also not known, and has been difficult to assess using traditional scales of neurologic impairment, such as the Expanded Disability Status Scale (EDSS). Even the MS Functional Composite (MSFC), the newest clinical outcome measure for MS trials, does not yet include an assessment of visual function. Our preliminary data from an ongoing cross-sectional study of visual function in MS at the University of Pennsylvania provide strong evidence that, among 5 candidate vision tests, contrast letter acuity and contrast sensitivity best distinguish MS patients from disease-free controls, even following detailed refractions and analyses accounting for age. The capacity for visual function tests to predict changes in MS disease longitudinally, however, has not been examined in clinically heterogeneous cohorts. This proposal will accomplish three specific aims: Aim 1: Define the longitudinal visual profile of MS in a large cohort, and determine which visual function tests demonstrate the greatest degree responsiveness to change over time. Aim 2: Determine the relation of baseline visual function test scores to subsequent neurologic impairment, and the relation between changes in visual function and changes in neurologic impairment over time, as measured by the EDSS and MSFC. Aim 3: Examine the relation of baseline visual function test scores to health-related quality of life (HRQOL) at subsequent study visits, and the relation between changes in visual function and changes in HRQOL over time, as measured by the 25-Item National Eye Institute Visual Function Questionnaire (VFQ-25) and the Multiple Sclerosis Quality of Life Inventory (MSQLI). Collectively, these aims will lead to the identification of sensitive, valid, and clinically practical visual function tests that are responsive to changes in MS disease over time, and will be capable of capturing treatment effects in future trials of MS therapies.